A phase 2 study of the first imipridone ONC201, a selective DRD2 antagonist for oncology, administered every three weeks in recurrent glioblastoma.
A phase 2 study of the first imipridone ONC201, a selective DRD2 antagonist for oncology, administered every three weeks in recurrent glioblastoma.
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DOI：
10.18632/oncotarget.17837
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发表时间：
2017-10-03
期刊：
影响因子：
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通讯作者：
Batchelor TT
中科院分区：
文献类型：
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作者：
Arrillaga-Romany I;Chi AS;Allen JE;Oster W;Wen PY;Batchelor TT
ONC201 是一种口服小分子选择性 G 蛋白偶联受体 DRD2 拮抗剂，可通过整合应激反应激活和 Akt/ERK 失活导致肿瘤细胞中不依赖于 p53 的细胞凋亡。我们进行了一项 II 期研究，入组了 17 名未接受贝伐珠单抗治疗的复发性 IDH1/2 WT 胶质母细胞瘤患者，每三周接受 625 毫克 ONC201 治疗。中位 OS 为 41.6 周，其中 OS6 为 71%，OS9 为 53%。 17名患者中有7名还活着。 PFS6 为 11.8%，其中两名患者仍在研究中，并继续接受 ONC201 超过 12 个月。其中一名患有 H3.3 K27M 突变的继发性胶质母细胞瘤患者获得了持久的客观缓解，其中一个病灶消退了 85%，第二个病灶消退了 76%。第二名继续接受 ONC201 治疗超过 12 个月的患者在参加本试验后在再次切除后仍保持无病状态。没有发生与药物相关的严重不良事件或因毒性而停止治疗。给药后 2 小时的血浆 PK 为 2.6 ug/mL，观察到血清催乳素诱导作为靶标参与的替代标志物，并且 DRD2 在所有评估的存档肿瘤样本中表达。总之，ONC201 具有良好的耐受性，并且在复发性胶质母细胞瘤患者中可能具有单药活性。
ONC201 is an oral, small molecule selective antagonist of the G protein-coupled receptor DRD2 that causes p53-independent apoptosis in tumor cells via integrated stress response activation and Akt/ERK inactivation. We performed a Phase II study that enrolled 17 patients with recurrent, bevacizumab-naïve, IDH1/2 WT glioblastoma who received 625mg ONC201 every three weeks. Median OS was 41.6 weeks with OS6 of 71% and OS9 of 53%. Seven of 17 patients are alive. PFS6 was 11.8% with two patients remaining on study who continue to receive ONC201 for >12 months. One of these patients had a durable objective response with a secondary glioblastoma possessing a H3.3 K27M mutation, exhibiting regression by 85% in one lesion and 76% in the second lesion. The second patient who continues to receive ONC201 for >12 months remains disease-free after enrolling on this trial following a re-resection. No drug-related SAEs or treatment discontinuation due to toxicity occurred. Plasma PK at 2 hours post-dose was 2.6 ug/mL, serum prolactin induction was observed as a surrogate marker of target engagement, and DRD2 was expressed in all evaluated archival tumor specimens. In summary, ONC201 is well tolerated and may have single agent activity in recurrent glioblastoma patients.